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Polycystic Ovary Syndrome: the Epigenetics Behind the Disease

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Abstract

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, affecting approximately 5–20% of women of reproductive age. PCOS is a multifactorial, complex, and heterogeneous disease, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries, which may lead to impaired fertility. Besides the reproductive outcomes, multiple comorbidities, such as metabolic disturbances, insulin resistance, obesity, diabetes, and cardiovascular disease, are associated with PCOS. In addition to the clear genetic basis, epigenetic alterations may also play a central role in PCOS outcomes, as environmental and hormonal alterations directly affect clinical manifestations and PCOS development. Here, we highlighted the epigenetic modifications in the multiplicity of clinical manifestations, as well as environmental epigenetic disruptors, as intrauterine hormonal and metabolic alterations affecting embryo development and the adulthood lifestyle, which may contribute to PCOS development. Additionally, we also discussed the new approaches for future studies and potential epigenetic biomarkers for the treatment of associated comorbidities and improvement in quality of life of women with PCOS.

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References

  1. Azziz R, Dumesic DA, Goodarzi MO. Polycystic ovary syndrome: an ancient disorder? Fertil Steril. 2011;95:1544–8.

    Article  PubMed  Google Scholar 

  2. Vallisneri A. Storia della generazione dell’uomo e dell’animale; 1721. Cited in Cooke ID, Lunenfeld B. Res Clin Forums. 1989;11:109–13.

    Google Scholar 

  3. Szydlarska D, Machaj M, Jakimiuk A. History of discovery of polycystic ovary syndrome. Adv Clin Exp Med. 2017:555–8.

  4. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29:181–91.

    Article  Google Scholar 

  5. Zawadzki J, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, HR G, FP H, GR M, editors. Polycystic ovary syndr. Boston, MA: Blackwell Scientific; 1992. p. 377–384.

  6. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19–25.

    Article  Google Scholar 

  7. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. J Clin Endocrinol Metab. 2006;91:4237–45.

    Article  CAS  PubMed  Google Scholar 

  8. Carmina E, Lobo RA. Use of fasting blood to assess the prevalence of insulin resistance in women with polycystic ovary syndrome. Fertil Steril. 2004;82:661–5.

    Article  PubMed  Google Scholar 

  9. Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010:41.

  10. Azziz R, Marin C, Hoq L, Badamgarav E, Song P. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life Span. J Clin Endocrinol Metab. 2005:4650–8.

  11. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JSE, Legro RS, et al. Polycystic ovary syndrome. Nat. Rev. Dis. Prim. 2016:1–18.

  12. Sagvekar P, Kumar P, Mangoli V, Desai S, Mukherjee S. DNA methylome profiling of granulosa cells reveals altered methylation in genes regulating vital ovarian functions in polycystic ovary syndrome. Clin Epigenetics. 2019;11:1–16.

    Article  CAS  Google Scholar 

  13. Amato P, Simpson JL. The genetics of polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004;18:707–18.

    Article  PubMed  Google Scholar 

  14. Kahsar-Miller MD, Nixon C, Boots LR, Go RC, Azziz R. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil Steril. 2001;75:53–8.

    Article  CAS  PubMed  Google Scholar 

  15. Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006;91:2100–4.

    Article  CAS  PubMed  Google Scholar 

  16. Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun. 2015;6:1–12.

  17. Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008;40:638–45.

  18. Hakonarson H, Qu HQ, Bradfield JP, Marchand L, Kim CE, Glessner JT, et al. A novel susceptibility locus for type 1 diabetes on chr12q13 identified by a genome-wide association study. Diabetes. 2008;57:1143–6.

  19. Capalbo A, Sagnella F, Apa R, Fulghesu AM, Lanzone A, Morciano A, et al. The 312N variant of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR) confers up to 2.7-fold increased risk of polycystic ovary syndrome in a Sardinian population. Clin Endocrinol (Oxf). 2012;77:113–9.

  20. Almawi WY, Hubail B, Arekat DZ, Al-Farsi SM, Al-Kindi SK, Arekat MR, et al. Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome. J Assist Reprod Genet. 2015;32:607–14.

  21. Shoham Z, Jacobs HS, Insler V. Luteinizing hormone: its role, mechanism of action, and detrimental effects when hypersecreted during the follicular phase. Fertil Steril. 1993;59:1153–61.

  22. Mason H, Franks S. Local control of ovarian steroidogenesis. Baillieres Clin Obstet Gynaecol. 1997;11:261–79.

  23. Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet. 2012;44:1020–5.

  24. Day FR, Hinds DA, Tung JY, Stolk L, Styrkarsdottir U, Saxena R, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun. 2015;6:1–7.

  25. Goodarzi MO, Jones MR, Li X, Chua AK, Garcia OA, Chen YDI, et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet. 2012;49:90–5.

  26. Jamnongjit M, Gill A, Hammes SR. Epidermal growth factor receptor signaling is required for normal ovarian steroidogenesis and oocyte maturation. PNAS. 2005.

  27. LaVoie HA. The GATA-keepers of ovarian development and folliculogenesis. Biol. Reprod. 2014:38–9.

  28. Qin K, Ehrmann DA, Cox N, Refetoff S, Rosenfield RL. Identification of a functional polymorphism of the human type 5 17β-hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:270–6.

  29. Ju R, Wu W, Fei J, Qin Y, Tang Q, Wu D, et al. Association analysis between the polymorphisms of HSD17B5 and HSD17B6 and risk of polycystic ovary syndrome in Chinese population. Eur J Endocrinol. 2015;172:227–33.

    Article  CAS  PubMed  Google Scholar 

  30. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010;42:579–89.

    Article  CAS  PubMed  Google Scholar 

  31. Reddy KR, Deepika MLN, Supriya K, Latha KP, Rao SSL, Rani VU, et al. CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India. J Assist Reprod Genet. 2014;31:857–63.

    Article  PubMed  Google Scholar 

  32. Tucci S, Futterweit W, Concepcion ES, Greenberg DA, Villanueva R, Davies TFTY. Evidence for association of polycystic ovary syndrome in caucasian women with a marker at the insulin receptor gene locus. J Clin Endocrinol Metab. 2001;86:446–9.

    Article  CAS  PubMed  Google Scholar 

  33. Zi-jiang Chen, Shi Y, Zhao Y, Li Y, Tang R, Zhao L, et al. Correlation between single nucleotide polymorphism of insulin receptor gene with polycystic ovary syndrome. Chin J Obs Gynecol. 2004;39:582–5.

  34. Lee EJ, Oh B, Lee JY, Kimm K, Lee SH, Baek KH. A novel single nucleotide polymorphism of INSR gene for polycystic ovary syndrome. Fertil Steril. 2008;89:1213–20.

  35. Goodarzi MO, Louwers YV, Taylor KD, Jones MR, Cui J, Kwon S, et al. Replication of association of a novel insulin receptor gene polymorphism with polycystic ovary syndrome. Fertil Steril. 2011;95:1736–41.

  36. Ju R, Wu W, Tang Q, Wu D, Xia Y, Wu J, et al. Association analysis between the polymorphisms of HSD11B1 and H6PD and risk of polycystic ovary syndrome in Chinese population. PLoS One. 2015;10:1–10.

  37. Sudo S, Kudo M, Wada SI, Sato O, Hsueh AJW, Fujimoto S. Genetic and functional analyses of polymorphisms in the human FSH receptor gene. Mol Hum Reprod. 2002;8:893–9.

    Article  CAS  PubMed  Google Scholar 

  38. Li T, Zhao H, Zhao X, Zhang B, Cui L, Shi Y, et al. Identification of YAP1 as a novel susceptibility gene for polycystic ovary syndrome. J Med Genet. 2012;49:254–7.

    Article  CAS  PubMed  Google Scholar 

  39. Jones MR, Wilson SG, Mullin BH, Mead R, Watts GF, Stuckey BGA. Polymorphism of the follistatin gene in polycystic ovary syndrome. Mol Hum Reprod. 2007;13:237–41.

    Article  CAS  PubMed  Google Scholar 

  40. Raja-Khan N, Kunselman AR, Demers LM, Ewens KG, Spielman RS, Legro RS. A variant in the fibrillin-3 gene is associated with TGF-β and inhibin B levels in women with polycystic ovary syndrome. Fertil Steril. 2010;94:2916–9.

    Article  CAS  PubMed  Google Scholar 

  41. Lin Y, Dion V, Wilson JH. Transcription and triplet repeat instability. Second Edi. Genet. Instab. Neurol. Dis. Second Ed. Elsevier Inc; 2006.

  42. Lin LH, Baracat MCP, MacIel GAR, Soares JM, Baracat EC. Androgen receptor gene polymorphism and polycystic ovary syndrome. Int J Gynecol Obstet. 2013;120:115–8.

    Article  CAS  Google Scholar 

  43. Li Q, Du J, Feng R, Xu Y, Wang H, Sang Q, et al. A possible new mechanism in the pathophysiology of polycystic ovary syndrome (PCOS): the discovery that leukocyte telomere length is strongly associated with PCOS. J Clin Endocrinol Metab. 2014;99:234–40.

    Article  Google Scholar 

  44. Pedroso DCC, Miranda-Furtado CL, Kogure GS, Meola J, Okuka M, Silva C, et al. Inflammatory biomarkers and telomere length in women with polycystic ovary syndrome. Fertil Steril. 2015;103:542–547.e2.

    Article  CAS  PubMed  Google Scholar 

  45. Wei D, Xie J, Yin B, Hao H, Song X, Liu Q, et al. Significantly lengthened telomere in granulosa cells from women with polycystic ovarian syndrome (PCOS). J Assist Reprod Genet. 2017;34:861–6.

    Article  PubMed  Google Scholar 

  46. Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, et al. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114:2236–43.

    Article  CAS  PubMed  Google Scholar 

  47. Welt CK, Duran JM. The genetics of polycystic ovary syndrome. Semin Reprod Med. 2014;32:177–82.

    Article  CAS  PubMed  Google Scholar 

  48. Lee HJ, Hore TA, Reik W. Reprogramming the methylome: erasing memory and creating diversity. Cell Stem Cell. 2014:710–9.

  49. Waddington CH. Canalization of development and the inheritance of acquired characters. Nat Publ Gr. 1942;150:563–5.

    Google Scholar 

  50. Monk D, Mackay DJG, Eggermann T, Maher ER, Riccio A. Genomic imprinting disorders: lessons on how genome, epigenome and environment interact. Nat Rev Genet Springer US. 2019;20:235–48.

    Article  CAS  Google Scholar 

  51. Nageshwaran S, Festenstein R. Epigenetics and triplet-repeat neurological diseases. Front Neurol. 2015:1–9.

  52. Nebbioso A, Tambaro FP, Dell’Aversana C, Altucci L. Cancer epigenetics: moving forward. PLoS Genet. 2018;14:1–25.

    Article  Google Scholar 

  53. Ling C, Rönn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab. 2019;29:1028–44.

    Article  CAS  PubMed  Google Scholar 

  54. Filippou P, Homburg R. Is foetal hyperexposure to androgens a cause of PCOS? Hum Reprod Update. 2017;23:421–32.

    Article  CAS  PubMed  Google Scholar 

  55. Dumesic DA, Goodarzi MO, Chazenbalk GD, Abbott DH. Intrauterine environment and polycystic ovary syndrome. Semin Reprod Med. 2014;32:159–65.

    Article  PubMed  Google Scholar 

  56. Gur EB. Fetal programming of polycystic ovary syndrome. World J Diabetes. 2015;6:936.

    Article  PubMed  Google Scholar 

  57. Wu XY, Li ZL, Wu CY, Liu YM, Lin H, Wang SH, et al. Endocrine traits of polycystic ovary syndrome in prenatally androgenized female Sprague-Dawley rats. Endocr J. 2010;57:201–9.

    Article  CAS  PubMed  Google Scholar 

  58. Zhu JQ, Zhu L, Liang XW, Xing FQ, Schatten H, Sun QY. Demethylation of LHR in dehydroepiandrosterone-induced mouse model of polycystic ovary syndrome. Mol Hum Reprod. 2010;16:260–6.

    Article  CAS  PubMed  Google Scholar 

  59. Padmanabhan V, Veiga-Lopez A. Sheep models of polycystic ovary syndrome phenotype. Mol Cell Endocrinol. 2013:8–20.

  60. Zhang D, Cong J, Shen H, Wu Q, Wu X. Genome-wide identification of aberrantly methylated promoters in ovarian tissue of prenatally androgenized rats. Fertil Steril. 2014;102:1458–67.

    Article  CAS  PubMed  Google Scholar 

  61. Xu N, Kwon S, Abbott DH, Geller DH, Dumesic DA, Azziz R, et al. Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS)-like phenotypes in prenatally androgenized rhesus monkeys. PLoS One. 2011;6:1–9.

    Article  Google Scholar 

  62. Das R, Hampton DD, Jirtle RL. Imprinting evolution and human health. Mamm. Genome. 2009:563–72.

  63. Duncan CG, Grimm SA, Morgan DL, Bushel PR, Bennett BD, Roberts JD, et al. Dosage compensation and DNA methylation landscape of the X chromosome in mouse liver. Sci Rep. 2018;8:1–17.

    Article  CAS  Google Scholar 

  64. Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011;25:1010–22.

    Article  CAS  PubMed  Google Scholar 

  65. Salehi Jahromi M, Hill JW, Ramezani Tehrani F, Zadeh-Vakili A. Hypomethylation of specific CpG sites in the promoter region of steroidogeneic genes (GATA6 and StAR) in prenatally androgenized rats. Life Sci Elsevier Inc. 2018;207:105–9.

    CAS  Google Scholar 

  66. Nilsson E, Klukovich R, Sadler-Riggleman I, Beck D, Xie Y, Yan W, et al. Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufiency. Epigenetics. 2018;13:875–95.

    Article  PubMed  Google Scholar 

  67. Albrecht ED, Pepe GJ. Estrogen regulation of placental angiogenesis and fetal ovarian development during primate pregnancy. Int J Dev Biol. 2010;54:397–407.

    Article  CAS  PubMed  Google Scholar 

  68. Fowler PA, Anderson RA, Saunders PT, Kinnell H, Mason JI, Evans DB, et al. Development of steroid signaling pathways during primordial follicle formation in the human fetal ovary. J Clin Endocrinol Metab. 2011;96:1754–62.

    Article  CAS  PubMed  Google Scholar 

  69. Fenichel P, Rougier C, Hieronimus S, Chevalier N. Le syndrome des ovaires polykystiques, est-il d’origine génétique, environnementale ou les deux ? Ann. Endocrinol. (Paris). Elsevier Masson SAS. 2017:176–85.

  70. Steckler T, Wang J, Bartol FF, Roy SK, Padmanabhan V. Fetal programming: prenatal testosterone treatment causes intrauterine growth retardation, reduces ovarian reserve and increases ovarian follicular recruitment. Endocrinology. 2005;146:3185–93.

    Article  CAS  PubMed  Google Scholar 

  71. Xu N, Chua AK, Jiang H, Liu NA, Goodarzi MO. Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes. Mol Endocrinol Endocrine Soc. 2014;28:1329–36.

    Article  Google Scholar 

  72. Echiburú B, Milagro F, Crisosto N, Pérez-Bravo F, Flores C, Arpón A, et al. DNA methylation in promoter regions of genes involved in the reproductive and metabolic function of children born to women with PCOS. Epigenetics Taylor Francis. 2020;00:1–17.

    Google Scholar 

  73. Melo AS, Vieira CS, Barbieri MA, Rosa-E-Silva ACJS, Silva AAM, Cardoso VC, et al. High prevalence of polycystic ovary syndrome in women born small for gestational age. Hum Reprod. 2010;25:2124–31.

    Article  CAS  PubMed  Google Scholar 

  74. Cherskov A, Pohl A, Allison C, Zhang H, Payne RA, Baron-Cohen S. Polycystic ovary syndrome and autism: a test of the prenatal sex steroid theory. Transl Psychiatry. 2018;8:1–10.

    Article  Google Scholar 

  75. van den Berg IM, Laven JSE, Stevens M, Jonkers I, Galjaard RJ, Gribnau J, et al. X Chromosome inactivation is initiated in human preimplantation embryos. Am J Hum Genet. 2009;84:771–9.

    Article  PubMed  Google Scholar 

  76. Hickey T, Chandy A, Norman RJ. The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87:161–5.

    Article  CAS  PubMed  Google Scholar 

  77. Hickey TE, Legro RS, Norman RJ. Brief Report: Epigenetic modification of the X chromosome influences susceptibility to polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:2789–91.

    Article  CAS  PubMed  Google Scholar 

  78. Shah NA, Antoine HJ, Pall M, Taylor KD, Azziz R, Goodarzi MO. Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:1939–45.

    Article  CAS  PubMed  Google Scholar 

  79. Dasgupta S, Sirisha PVS, Neelaveni K, Anuradha K, Reddy AG, Thangaraj K, et al. Androgen receptor cag repeat polymorphism and epigenetic influence among the south indian women with polycystic ovary syndrome. PLoS One. 2010;5:1–8.

    Article  Google Scholar 

  80. Laisk T, Haller-Kikkatalo K, Laanpere M, Jakovlev Ü, Peters M, Karro H, et al. Androgen receptor epigenetic variations influence early follicular phase gonadotropin levels. Acta Obstet Gynecol Scand. 2010;89:1557–63.

    Article  CAS  PubMed  Google Scholar 

  81. Xu N, Azziz R, Goodarzi MO. Epigenetics in polycystic ovary syndrome: a pilot study of global DNA methylation. Fertil Steril. 2010;94:781–3.

    Article  CAS  PubMed  Google Scholar 

  82. Wang P, Zhao H, Li T, Zhang W, Wu K, Li M, et al. Hypomethylation of the LH/choriogonadotropin receptor promoter region is a potential mechanism underlying susceptibility to polycystic ovary syndrome. Endocrinology. 2014;155:1445–52.

    Article  PubMed  Google Scholar 

  83. Sagvekar P, Mangoli V, Desai S, Patil A, Mukherjee S. LINE1 CpG-DNA hypomethylation in granulosa cells and blood leukocytes is associated with PCOS and related traits. J Clin Endocrinol Metab. 2017;102:1396–405.

    Article  PubMed  Google Scholar 

  84. Qu F, Wang FF, Yin R, Ding GL, El-prince M, Gao Q, et al. A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells. J Mol Med. 2012;90:911–23.

    Article  CAS  PubMed  Google Scholar 

  85. Pan JX, Tan YJ, Wang FF, Hou NN, Xiang YQ, Zhang JY, et al. Aberrant expression and DNA methylation of lipid metabolism genes in PCOS: a new insight into its pathogenesis. Clin Epigenetics. 2018;10:1–12.

    Article  Google Scholar 

  86. Jiang L, Le XJK, Cui JQ, Wei D, Yin BL, Zhang YN, et al. Promoter methylation of yes-associated protein (YAP1) gene in polycystic ovary syndrome. Med (US). 2017;96:1–6.

    Google Scholar 

  87. Yu YY, Sun CX, Liu YK, Li Y, Wang L, Zhang W. Genome-wide screen of ovary-specific DNA methylation in polycystic ovary syndrome. Fertil Steril Elsevier Inc. 2015;104:145–53.

    Article  CAS  Google Scholar 

  88. Yu YY, Sun CX, Liu YK, Li Y, Wang L, Zhang W. Promoter methylation of CYP19A1 gene in chinese polycystic ovary syndrome patients. Gynecol Obstet Invest. 2013;76:209–13.

    Article  CAS  PubMed  Google Scholar 

  89. Li D, Jiao J, Zhou YM, Wang XX. Epigenetic regulation of traf2- and nck-interacting kinase (Tnik) in polycystic ovary syndrome. Am J Transl Res. 2015;7:1152–60.

    PubMed  Google Scholar 

  90. Pruksananonda K, Wasinarom A, Sereepapong W, Sirayapiwat P, Rattanatanyong P, Mutirangura A. Epigenetic modification of long interspersed elements-1 in cumulus cells of mature and immature oocytes from patients with polycystic ovary syndrome. Clin Exp Reprod Med. 2016;43:82–9.

    Article  PubMed  Google Scholar 

  91. Huang X, Hao C, Shen X, Liu X, Shan Y, Zhang Y, et al. Differences in the transcriptional profiles of human cumulus cells isolated from MI and MII oocytes of patients with polycystic ovary syndrome. Reproduction. 2013;145:597–608.

    Article  CAS  PubMed  Google Scholar 

  92. Hosseini E, Shahhoseini M, Afsharian P, Karimian L, Ashrafi M, Mehraein F, et al. Role of epigenetic modifications in the aberrant CYP19A1 gene expression in polycystic ovary syndrome. Arch Med Sci. 2019;15:887–95.

    Article  CAS  PubMed  Google Scholar 

  93. Ting W, Yanyan Q, Jian H, Keqin H, Duan M. The relationship between insulin resistance and CpG island methylation of LMNA gene in polycystic ovary syndrome. Cell Biochem Biophys. 2013;67:1041–7.

    Article  PubMed  Google Scholar 

  94. Sang Q, Li X, Wang H, Wang H, Zhang S, Feng R, et al. Quantitative methylation level of the EPHX1 promoter in peripheral blood DNA is associated with polycystic ovary syndrome. PLoS One. 2014;9:1–7.

    Article  CAS  Google Scholar 

  95. Zhao H, Zhao Y, Ren Y, Li M, Li T, Li R, et al. Epigenetic regulation of an adverse metabolic phenotype in polycystic ovary syndrome: the impact of the leukocyte methylation of PPARGC1A promoter. Fertil Steril. 2017;107:467–474.e5.

    Article  CAS  PubMed  Google Scholar 

  96. Jones MR, Brower MA, Xu N, Cui J, Mengesha E, Chen YDI, et al. Systems genetics reveals the functional context of PCOS loci and identifies genetic and molecular mechanisms of disease heterogeneity. PLoS Genet. 2015;11:1–17.

    Article  Google Scholar 

  97. Lin L, Du T, Huang J, Huang LL, Yang DZ. Identification of differentially expressed microRNAs in the ovary of polycystic ovary syndrome with hyperandrogenism and insulin resistance. Chin Med J (Engl). 2015;128:169–74.

    Article  CAS  Google Scholar 

  98. Jiang L, Huang J, Li L, Chen Y, Chen X, Zhao X, et al. MicroRNA-93 promotes ovarian granulosa cells proliferation through targeting CDKN1A in polycystic ovarian syndrome. J Clin Endocrinol Metab Endocrine Soc. 2015;100:E729–38.

    Article  Google Scholar 

  99. Wu HL, Heneidi S, Chuang TY, Diamond MP, Layman LC, Azziz R, et al. The expression of the miR-25/93/106b family of micro-RNAs in the adipose tissue of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2014;99:1–9.

    Article  Google Scholar 

  100. Chen YH, Heneidi S, Lee JM, Layman LC, Stepp DW, Gamboa GM, et al. Mirna-93 inhibits glut4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes. 2013;62:2278–86.

    Article  CAS  PubMed  Google Scholar 

  101. Sang Q, Yao Z, Wang H, Feng R, Wang H, Zhao X, et al. Identification of MicroRNAs in human follicular fluid: characterization of microRNAs that govern steroidogenesis in vitro and are associated with polycystic ovary syndrome in vivo. J Clin Endocrinol Metab. 2013;98:3068–79.

    Article  CAS  PubMed  Google Scholar 

  102. Roth LW, McCallie B, Alvero R, Schoolcraft WB, Minjarez D, Katz-Jaffe MG. Altered microRNA and gene expression in the follicular fluid of women with polycystic ovary syndrome. J Assist Reprod Genet. 2014;31:355–62.

    Article  PubMed  Google Scholar 

  103. Long W, Zhao C, Ji C, Ding H, Cui Y, Guo X, et al. Characterization of serum microRNAs profile of PCOS and identification of novel non-invasive biomarkers. Cell Physiol Biochem. 2014;33:1304–15.

    Article  CAS  PubMed  Google Scholar 

  104. Murri M, Insenser M, Fernández-Durán E, San-Millán JL, Escobar-Morreale HF. Effects of polycystic ovary syndrome (PCOS), sex hormones, and obesity on circulating miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 expression. J Clin Endocrinol Metab. 2013;98:1835–44.

    Article  Google Scholar 

  105. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45:D362–8.

    Article  CAS  PubMed  Google Scholar 

  106. Vázquez-martínez ER, Gómez-viais YI, García-gómez E, Reyes-mayoral C, Reyes-muñoz E, Camacho-arroyo I, et al. DNA methylation in the pathogenesis of polycystic ovary syndrome. Reproduction. 2019;158:R27–40.

    Article  PubMed  Google Scholar 

  107. Li S, Zhu D, Duan H, Ren A, Glintborg D, Andersen M, et al. Differential DNA methylation patterns of polycystic ovarian syndrome in whole blood of Chinese women. Oncotarget. 2017;8:20656–66.

    Article  PubMed  Google Scholar 

  108. Shen H ran, Qiu L hua, Zhang Z qing, Qin Y yuan, Cao C, Di W. Genome-wide methylated DNA immunoprecipitation analysis of patients with polycystic ovary syndrome. PLoS One. 2013;8:1–10.

  109. Kokosar M, Benrick A, Perfilyev A, Fornes R, Nilsson E, Maliqueo M, et al. Epigenetic and transcriptional alterations in human adipose tissue of polycystic ovary syndrome. Sci Rep. 2016;6:1–17.

    Google Scholar 

  110. Wang XX, Wei JZ, Jiao J, Jiang SY, Yu DH, Li D. Genome-wide DNA methylation and gene expression patterns provide insight into polycystic ovary syndrome development. Oncotarget. 2014;5:6603–10.

    Article  PubMed  Google Scholar 

  111. Salehi M, Bravo-Vera R, Sheikh A, Gouller A, Poretsky L. Pathogenesis of polycystic ovary syndrome: what is the role of obesity? Metabolism. 2004;53:358–76.

    Article  CAS  PubMed  Google Scholar 

  112. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.

    Article  CAS  PubMed  Google Scholar 

  113. Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. Nat Publ Group. 2016;17:47–62.

    Article  CAS  Google Scholar 

  114. Lin H, Xing W, Li Y, Xie Y, Tang X, Zhang Q. Downregulation of serum long noncoding RNA GAS5 may contribute to insulin resistance in PCOS patients. Gynecol Endocrinol. 2018;34:784–8.

    Article  CAS  PubMed  Google Scholar 

  115. Qin L, Huang CC, Yan XM, Wang Y, Li ZY, Wei XC. Long non-coding RNA h19 is associated with polycystic ovary syndrome in Chinese women: a preliminary study. Endocr J. 2019;66:587–95.

    Article  CAS  PubMed  Google Scholar 

  116. Makrinou E, Drong AW, Christopoulos G, Lerner A, Chapa-Chorda I, Karaderi T, et al. Genome-wide methylation profiling in granulosa lutein cells of women with polycystic ovary syndrome (PCOS). Mol Cell Endocrinol Elsevier. 2020;500:1–11.

    Google Scholar 

  117. Barth TK, Imhof A. Fast signals and slow marks: the dynamics of histone modifications. Trends Biochem Sci Elsevier Ltd. 2010;35:618–26.

    Article  CAS  Google Scholar 

  118. Eini F, Novin MG, Joharchi K, Hosseini A, Nazarian H, Piryaei A, et al. Intracytoplasmic oxidative stress reverses epigenetic modifications in polycystic ovary syndrome. Reprod Fertil Dev. 2017;29:2313–23.

    Article  CAS  PubMed  Google Scholar 

  119. Xu B, Zhang YW, Tong XH, Liu YS. Characterization of microRNA profile in human cumulus granulosa cells: identification of microRNAs that regulate Notch signaling and are associated with PCOS. Mol Cell Endocrinol Elsevier Ireland Ltd. 2015;404:26–36.

    Article  CAS  Google Scholar 

  120. Huang X, Hao C, Bao H, Wang M, Dai H. Aberrant expression of long noncoding RNAs in cumulus cells isolated from PCOS patients. J Assist Reprod Genet. 2016;33:111–21.

    Article  PubMed  Google Scholar 

  121. Huang X, Pan J, Wu B, Teng X. Construction and analysis of a lncRNA (PWRN2)-mediated ceRNA network reveal its potential roles in oocyte nuclear maturation of patients with PCOS. Reprod Biol Endocrinol. 2018;16:1–13.

    Article  Google Scholar 

  122. Liu YD, Li Y, Feng SX, Ye DS, Chen X, Zhou XY, et al. Long noncoding RNAs: potential regulators involved in the pathogenesis of polycystic ovary syndrome. Endocrinology. 2017;158:3890–9.

    Article  CAS  PubMed  Google Scholar 

  123. Zhao J, Huang J, Geng X, Chu W, Li S, Chen ZJ, et al. Polycystic ovary syndrome: Novel and hub lncRNAs in the insulin resistance-associated lncRNA–mRNA network. Front Genet. 2019;10:1–12.

    Article  Google Scholar 

  124. Zhao J, Xu J, Wang W, Zhao H, Liu H, Liu X, et al. Long non-coding RNA LINC-01572:28 inhibits granulosa cell growth via a decrease in p27 (Kip1) degradation in patients with polycystic ovary syndrome. EBioMedicine Authors. 2018;36:526–38.

    Article  Google Scholar 

  125. Wu G, Yang Z, Chen Y, Li X, Yang J, Yin T. Downregulation of Lnc-OC1 attenuates the pathogenesis of polycystic ovary syndrome. Mol Cell Endocrinol, Elsevier. 2020;506:1–7.

    Article  Google Scholar 

  126. Xia Y, Shen S, Zhang X, Deng Z, Xiang Z, Wang H, et al. Epigenetic pattern changes in prenatal female Sprague-Dawley rats following exposure to androgen. Reprod Fertil Dev. 2015;28:1414–23.

    Article  Google Scholar 

  127. Jiao J, Shi B, Wang T, Fang Y, Cao T, Zhou Y, et al. Characterization of long non-coding RNA and messenger RNA profiles in follicular fluid from mature and immature ovarian follicles of healthy women and women with polycystic ovary syndrome. Hum Reprod. 2018;33:1735–48.

    Article  CAS  PubMed  Google Scholar 

  128. Ding Y, Xia BH, Zhang CJ, Zhuo GC. Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome. Am J Transl Res. 2017;9:2984–96.

    CAS  PubMed  Google Scholar 

  129. Zhuo G, Ding Y, Feng G, Yu L, Jiang Y. Analysis of mitochondrial DNA sequence variants in patients with polycystic ovary syndrome. Arch Gynecol Obstet. 2012;286:653–9.

    Article  CAS  PubMed  Google Scholar 

  130. Reddy TV, Govatati S, Deenadayal M, Sisinthy S, Bhanoori M. Impact of mitochondrial DNA copy number and displacement loop alterations on polycystic ovary syndrome risk in south Indian women. Mitochondrion Elsevier. 2019;44:35–40.

    Article  CAS  Google Scholar 

  131. Ding Y, Xia BH, Zhang CJ, Zhuo GC. Mitochondrial tRNALeu(UUR) C3275T, tRNAGln T4363C and tRNALys A8343G mutations may be associated with PCOS and metabolic syndrome. Gene. 2018;642:299–306.

    Article  CAS  PubMed  Google Scholar 

  132. Reddy TV, Govatati S, Deenadayal M, Shivaji S, Bhanoori M. Polymorphisms in the TFAM and PGC1-α genes and their association with polycystic ovary syndrome among South Indian women. Gene, Elsevier. 2018;641:129–36.

    Article  CAS  PubMed  Google Scholar 

  133. Zhao H, Zhao Y, Li T, Li M, Li J, Li R, et al. Metabolism alteration in follicular niche: the nexus among intermediary metabolism, mitochondrial function, and classic polycystic ovary syndrome. Free Radic Biol Med, Elsevier. 2015;86:295–307.

    Article  CAS  PubMed  Google Scholar 

  134. Cree-Green M, Rahat H, Newcomer BR, Bergman BC, Brown MS, Coe GV, et al. Insulin resistance, hyperinsulinemia, and mitochondria dysfunction in nonobese girls with polycystic ovarian syndrome. J Endocr Soc. 2017;1:931–44.

    Article  CAS  PubMed  Google Scholar 

  135. Wang T, Zhang J, Hu M, Zhang Y, Cui P, Li X, et al. Differential expression patterns of glycolytic enzymes and mitochondria-dependent apoptosis in PCOS patients with endometrial hyperplasia, an early hallmark of endometrial cancer, in vivo and the impact of metformin in vitro. Int J Biol Sci. 2019;15:714–25.

    Article  CAS  PubMed  Google Scholar 

  136. Azhary JMK, Harada M, Takahashi N, Nose E, Kunitomi C, Koike H, et al. Endoplasmic reticulum stress activated by androgen enhances apoptosis of granulosa cells via induction of death receptor 5 in PCOS. Endocrinology. 2019;160:119–32.

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Acknowledgements

We would like to thank the members of the Human Reproduction Division at Department of Gynecology and Obstetrics of the Ribeirao Preto Medical School, University of Sao Paulo (FMRP-USP), and the members of the Laboratory of Experimental Oncology (LOE) at Drug Research and Development Center, Federal University of Ceara (NPDM-UFC). Fig. 2 was made in part using BioRender. The English was revised by Editage.

Funding

This study was supported by the Sao Paulo Research Foundation (FAPESP, Fundação de Amparo à Pesquisa do Estado de São Paulo) with the grant 2015/14031-0 (RMR) and fellowship 2012/11069-9 (CLMF), National Council for Scientific and Technological Development (CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico), Coordination for the Improvement of Higher Education Personnel (CAPES, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; Academic Excellence Program - PROEX and Graduate Support Program - PROAP) and by the National Institutes of Science and Technology (INCT, Institutos Nacionais de Ciência e Tecnologia).

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Av Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, SP, Brazil

    Matheus Credendio Eiras, Rui Alberto Ferriani, Rosana Maria Dos Reis & Cristiana Libardi Miranda Furtado

  2. Drug Research and Development Center, Department of Physiology and Pharmacology, Federal University of Ceara, Coronel Nunes de Melo, 1000, Rodolfo Teófilo, Fortaleza, 60430-275, CE, Brazil

    Daniel Pascoalino Pinheiro

  3. Drug Research and Development Center, Postgraduate Program in Medical and Surgical Sciences, Federal University of Ceara, Coronel Nunes de Melo, 1000, Rodolfo Teófilo, Fortaleza, CE, 60430-275, Brazil

    Kalil Andrade Mubarac Romcy & Cristiana Libardi Miranda Furtado

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  1. Matheus Credendio Eiras
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Correspondence to Rosana Maria Dos Reis or Cristiana Libardi Miranda Furtado.

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Eiras, M.C., Pinheiro, D.P., Romcy, K.A.M. et al. Polycystic Ovary Syndrome: the Epigenetics Behind the Disease. Reprod. Sci. 29, 680–694 (2022). https://doi.org/10.1007/s43032-021-00516-3

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